title: Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy.
abstract: Whereas it is generally perceived to be harmful, enhanced coagulation activation can also convey salutary effects. The high prevalence of the prothrombotic factor V Leiden (FVL) mutation in whites has been attributed to a positive selection pressure (eg, resulting from reduced blood loss or improved survival in sepsis). The consequences of enhanced coagulation activation, as observed in FVL carriers, on microvascular diabetic complications remain unknown. We therefore investigated the role of FVL in diabetic nephropathy. In heterozygous or homozygous diabetic FVL mice, albuminuria and indices of diabetic nephropathy were reduced compared with diabetic wild-type mice. This was associated with reduced glomerular apoptosis and preservation of podocytes in diabetic FVL-positive mice. In vitro, low-dose thrombin (50pM) prevented, whereas high-dose thrombin (20nM) aggravated, glucose-induced apoptosis in podocytes. In diabetic patients, the FVL mutation, but not the plasminogen activator inhibitor-1 4G/5G polymorphism, is associated with reduced albuminuria, which is consistent with a nephroprotective role of low but sustained thrombin generation. Consistently, anticoagulation of diabetic FVL-positive mice with hirudin abolished the nephroprotective effect. These results identify a nephroprotective function of low but sustained thrombin levels in FVL carriers, supporting a dual, context-dependent function of thrombin in chronic diseases.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.forename: Thati
authors.initials: T
authors.lastname: Madhusudhan
authors.forename: Tao
authors.initials: T
authors.lastname: He
authors.forename: Björn
authors.initials: B
authors.lastname: Hummel
authors.forename: Simone
authors.initials: S
authors.lastname: Schmidt
authors.forename: Ilya A
authors.initials: IA
authors.lastname: Vinnikov
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.forename: Muhammed
authors.initials: M
authors.lastname: Kashif
authors.forename: Sandra
authors.initials: S
authors.lastname: Muller-Krebs
authors.forename: Vedat
authors.initials: V
authors.lastname: Schwenger
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Gottfried
authors.initials: G
authors.lastname: Rudofsky
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001777:Blood Coagulation / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005165:Factor V / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D005947:Glucose / Q000009:adverse effects; D006801:Humans; D006943:Hyperglycemia / Q000150:complications; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D050199:Podocytes / Q000473:pathology*
chemical_list: C095381:factor V Leiden; D005165:Factor V; D005947:Glucose